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Introduction
Frontotemporal dementia (FTD) is comprised of a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders characterized by behavioral changes, executive dysfunction, and language impairment. Collectively, FTD represents the leading cause of early onset dementia and is particularly devastating to patients and their families because of early behavioral changes with erosion of personal relationships. Understanding the disease and its complexities, and educating the general public with respect to the course and causes of FTD are, therefore, acutely important.
The condition typically presents in mid to later life, with roughly 60% of patients presenting between 45 and 64 years of age [1]. Its prevalence ranges from 15 to 22 per 100,000 population-years. FTD is more common than Alzheimer’s disease (AD) in patients under the age of 60 years [2], and accounts for up to 20% of all patients with degenerative dementias [3, 4]. FTD is frequently hereditary, with up to 40% having a significant family history [5]. Non-genetic risk factors are yet to be identified.
The hallmark clinical features of FTD are progressive disturbances in behavior, cognition, and language. These are associated with atrophy and hypometabolism of the frontal and anterior temporal lobes, with relative sparing of the posterior regions of the brain. Clinically, FTD is divided into three subtypes based on the predominant early symptoms: behavioral or frontal-variant frontotemporal dementia (bvFTD), where there is progressive behavioral disturbance, executive dysfunction, and frontal lobe atrophy; non-fluent variant primary progressive aphasia (nfvPPA), characterized by motor speech and grammatical deficits, and a left frontal and insular predominant degeneration; and semantic variant PPA (svPPA), characterized by loss of word meaning and conceptual knowledge and left greater than right anterior temporal lobe atrophy. svPPA can also begin on the right side causing early deficits in emotion and the recognition of familiar faces. The three subtypes differ in prevalence, age of onset, sex distributions, genetic susceptibilities, co-associations with other degenerative conditions, and neuropathological features. There is major clinical, genetic, and pathological overlap between FTD and amyotrophic lateral sclerosis (ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy syndrome (PSP-S), and corticobasal syndrome (CBS). With disease progression, there is convergence between the different clinical subtypes, adding complexity in diagnostic accuracy.
The term frontotemporal lobar degeneration (FTLD) refers to the underlying pathological entities that cause FTD. The FTLD spectrum disorders are classified into three subtypes based on the identity of the protein aggregate: tau (FTLD-TAU), the 43-kD TAR-DNA-binding protein (FTLD-TDP), and the Fused in Sarcoma protein (FTLD-FUS). Table 9.1 summarizes the anatomic, pathologic, and genetic features of the FTD subtypes.
Notes: ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; PD, Parkinson’s disease; GRN, gene for progranulin; PSP, progressive supranuclear palsy; TDP, TAR DNA-binding protein.
A brief history of frontotemporal lobar degeneration
Arnold Pick first described a set of symptoms resulting from focal temporal atrophy that are now ascribed to FTLD [6]. While most of Pick’s original cases had focal temporal atrophy and would now be classified as having svPPA, he also described patients with focal frontal disease. His early work was supplemented by Alois Alzheimer, who noted that intraneuronal inclusions were seen upon pathological investigation of such patients [7]. Later, these inclusions were named Pick bodies. In the 1980s, investigators in England and Sweden began to study patients who suffered from focal degenerative disorders of the frontal and anterior temporal lobes in whom non-Alzheimer neuropathology was present [8, 9]. At the same time, Mesulam began to study patients with asymmetrical degeneration of the left hemisphere for whom he coined the term “primary progressive aphasia” (PPA). In both the symmetrical cases described as “FTD” and the asymmetrical left-sided cases characterized as PPA, non-AD pathology was often found.
With advances in neuroimaging in the late 1980s and early 1990s, patients with atrophy of the frontal and anterior temporal lobes, in conjunction with non-Alzheimer pathology, were found more readily; in approximately 80% of them, classical Pick bodies were not found [4, 10, 11], leading Arne Brun to coin the term “frontal lobe dementia of the non-Alzheimer-type.” By the early 1990s, many cases were reported in the USA [12, 13]. As similarities between the language and behavioral syndromes were observed at a pathological level, FTLD was used to capture this constellation of patients with focal frontotemporal clinical syndromes that were thought to be associated with non-Alzheimer pathology.
Further complicating efforts for a streamlined nomenclature syndrome, the overlap between FTLD and motor disorders became apparent. It was observed that FTD and ALS often coexisted in the same patients. They also shared the same pathology of TDP-43 inclusions. In addition, linking FTLD to atypical parkinsonian syndromes, there is significant and simultaneous degeneration of basal ganglia structures in FTLD populations, which often leads to the coexpression of parkinsonian features within all of the FTLD subtypes. In the case of nfvPPA, most patients demonstrate tau pathology with corticobasal degeneration (CBD), classical Pick’s disease, or progressive supranuclear palsy (PSP) at autopsy, but a minority show TDP-43 type A aggregates. By contrast, svPPA is usually associated with a specific subtype of TDP-43 called TDP-43 C.
Diagnosing frontotemporal dementia
It can be problematic to diagnose FTD with clinical accuracy, and in some instances FTD is difficult to distinguish from AD. Both AD and FTD produce a progressive dementia syndrome that can include memory deficits, executive dysfunction, and language impairment, and cause alterations in behavior [14]. Nevertheless, many distinguishing features exist. For instance, in patients with early AD, atrophy is most commonly seen in the medial temporal lobes, leading to episodic memory deficits, and an inability to learn new information [15]. As the frontal, parietal, and even occipital lobes become involved, other cognitive, social, emotional, and even perceptual impairments are observed [16].
By contrast, in FTD, neural degeneration starts in the frontal and anterior temporal lobes, and early symptoms include deficits in behavior, executive control or language function, with relatively intact episodic memory [17]. Studies have now shown that FTD can be reliably differentiated from AD during life based upon the characteristic patterns of decline [18, 19]. Even in specialized clinical centers, a small percentage of patients diagnosed with FTD show AD pathology.
In 1998, Neary and colleagues delineated research criteria for the diagnosis of the three clinical syndromes of FTD, which represented a major development in the field [20]. Later, it became apparent that these criteria required refinement. This led to the revised criteria proposed by an international consortium in 2011 [21] for the diagnosis of bvFTD (Table 9.2), as well as revised diagnostic criteria for the diagnosis of SD (Table 9.3) and PNFA (Table 9.4) [22] (now labeled as svPPA and nfvPPA). Diagnosis of svPPA and nfvPPA requires that the patient has a primary progressive aphasia (PPA), characterized by three features: aphasia is the most prominent clinical feature, is the principal cause of impaired daily activities, and is the most prominent deficit at symptom onset and at initial stages of the disease.
| I. | Neurodegenerative disease (required criterion) |
| A. | Progressive deterioration of behavior and/or cognition |
| II. | Possible bvFTD (three out of six required) |
| A. | Early behavioral disinhibition |
| B. | Early apathy or inertia |
| C. | Early loss of sympathy or empathy |
| D. | Early perseverative, stereotyped, or compulsive/ritualistic behavior |
| E. | Hyperorality and dietary changes |
| F. | Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions |
| III. | Probable bvFTD (all of the following required) |
| A. | Meets criteria for possible bvFTD |
| B. | Significant functional decline |
| C. | Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET) |
| IV. | bvFTD with definite FTLD pathology (A and either B or C required) |
| A. | Meets criteria for possible or probable bvFTD |
| B. | Histopathological evidence of FTLD on biopsy or at postmortem |
| C. | Presence of a known pathogenic mutation |
| V. | Exclusion criteria (A and C must be negative; C can be positive in possible in bvFTD but must be negative in probably bvFTD) |
| A. | Pattern of deficits is better accounted for by other nervous system or medical disorders |
| B. | Behavioral disturbance is better accounted for by a psychiatric diagnosis |
| C. | Biomarkers are strongly indicative of Alzheimer’s disease or other neurodegenerative process |
| I. | Clinical diagnosis of SD |
| Both of: | |
| 1. | Impaired confrontation naming |
| 2. | Impaired single-word comprehension |
| At least three of: | |
| 1. | Impaired object knowledge especially for low-frequency or low-familiarity items |
| 2. | Surface dyslexia or dysgraphia |
| 3. | Spared repetition |
| 4. | Spared speech production (grammar and motor speech) |
| II. | Imaging-supported SD |
| Both of: | |
| 1. | Clinical diagnosis of SD |
| 2. | Imaging shows one of: |
| a. Predominant anterior temporal lobe atrophy | |
| b. Predominant anterior temporal hypoperfusion or hypometabolism on SPECT or PET | |
| III. | SD with definite pathology |
| Clinical diagnosis of SD and either one of: | |
| 1. | Histopathologic evidence of a specific neurodegenerative pathology (e.g., FTLD-tau, FTLD-TDP, AD, other) |
| 2. | Presence of a known pathogenic mutation |
Notes: AD: Alzheimer’s disease; FTLD: frontotemporal lobar degeneration; PET: positron emission tomography; SD: semantic dementia; SPECT: single photon emission computed tomography; TDP: TAR-DNA-binding protein. [22]
| I. | Clinical diagnosis of PNFA |
| At least one of: | |
| 1. | Agrammatism in language production |
| 2. | Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech) |
| At least two of: | |
| 1. | Impaired comprehension of syntactically complex sentences |
| 2. | Spared single-word comprehension |
| 3. | Spared object knowledge |
| II. | Imaging-supported PNFA |
| Both of: | |
| 1. | Clinical diagnosis of PNFA |
| 2. | Imaging shows one or more of: |
| a. predominant left posterior frontoinsular atrophy on MRI, or | |
| b. predominant left posterior frontoinsular hypoperfusion or hypometabolism on SPECT or PET | |
| III. | PNFA with definite pathology |
| Clinical diagnosis of PNFA and either one of: | |
| 1. | Histopathologic evidence of a specific neurodegenerative pathology (e.g., FTLD-tau, FTLD-TDP, AD, other) |
| 2. | Presence of a known pathogenic mutation |
Notes: AD: Alzheimer’s disease; FTLD: frontotemporal lobar degeneration; MRI: magnetic resonance imaging; PET: positron emission tomography; PNFA: progressive non-fluent aphasia; SPECT: single positron emission computed tomography; TDP: TAR-DNA-binding protein. [22]
Behavioral variant frontotemporal dementia
The behavioral subtype of FTD accounts for approximately 56% of all FTLD [23, 24]. In some studies this subtype is male predominant, while in others the strong male predominance is not seen; bvFTD has the earliest age of onset (around 58 years at diagnosis), progresses most rapidly from time of diagnosis (3.4 years from diagnosis to death), has the highest genetic susceptibility (up to 20% show an autosomal dominant pattern of inheritance), and has a strong association with ALS. At our University of California at San Francisco (UCSF) clinic, patients with FTD are equally divided between those with TDP-43 and those with tau inclusions postmortem. A small percentage of patients show aggregates of the FUS protein. Additionally, it is now recognized that patients who carry the C9ORF72 mutation that leads to FTD-ALS also carry dipeptides, generated from the long C9 hexanucleotide repeat.
The first symptoms of bvFTD include alterations in social decorum and personal regulation with disinhibition, apathy, overeating, loss of empathy, and impairment in judgment and insight. In addition, deficits in executive functioning such as perseverative behaviors, and difficulties with planning, organizing, task switching, and generating ideas are seen. These early symptoms are often misconstrued as midlife issues or psychiatric problems. Sadly, unlike in AD, where social decorum is spared and family and acquaintances remain sympathetic, in FTD, patients are often resented because of their deficits in social modulation.
Anatomically, bvFTD typically begins in the anterior cingulate, orbitofrontal, and anterior insular regions of the frontal lobes, areas that modulate emotion, reward-mediated behaviors, and drive. Structural and functional imaging studies typically show greater abnormalities in the right than the left frontal regions. Often the atrophy in these areas is evident on the first visit to the neurologist. As the disease progresses, dorsolateral prefrontal cortical involvement becomes apparent and patients begin to exhibit abnormalities in executive control.
Approximately 15% of bvFTD patients develop ALS [25], with features including weakness, atrophy, fasciculations, upper motor neuron signs, bulbar symptoms, and pseudobulbar affect. These patients are referred to as FTD with ALS (FTD-ALS). The overlap between FTD and ALS is increasingly appreciated as most of these patients have FTLD-TDP pathology and as many as 50% of patients with ALS show signs of executive dysfunction on testing [26]. In 2011 it was discovered that the major gene responsible for both familial forms of FTD, FTD-ALS, and ALS is a long hexanucleotide repeat in the intron region of the C9 gene.
Semantic variant primary progressive aphasia
The svPPA subtype is a temporally predominant syndrome that attacks, often asymmetrically, either the left or the right anterior temporal lobe and accounts for approximately 20% of all patients with svPPA. Patients with svPPA have a slightly older age of onset (around 59 years), show the slowest rate of progression (5.2 years from diagnosis to death), and are less likely to have an autosomal dominant pattern of inheritance. We have found approximately 15% of patients with svPPA have a history of autoimmune disease, with rare disorders such as Sjogren syndrome, sarcoidosis, celiac disease, and vitiligo over-represented in this population. In addition, left-handedness is also more common in svPPA. On postmortem examination, these patients usually show ubiquitin–TDP-43 type C inclusions [23, 24].
Patients with left-sided svPPA begin with word-finding difficulty, often with nouns more than verbs. Category specificity for these naming deficits is common, with knowledge regarding animals lost before tool knowledge. With svPPA, the specific layering of meaning that surrounds a given word is lost and patients substitute specific words for superordinate categories. For example, an “osprey” may become an “eagle,” then a “bird,” next an “animal,” and finally a “thing” before the word and concept are lost entirely. As svPPA progresses, speech remains fluent but the anomia worsens and patients begin to show trouble also in recognizing words. Compulsive interests in visually appealing objects emerge. As the disease spreads to the right side, patients begin to have problems recognizing emotions in others and lose the ability to recognize faces or people or buildings that they once knew. Eventually prosopagnosia and multimodality agnosia for objects develop; even though a patient can see, feel, and touch an item, he/she is unable to conjure up its name or recognize its function.
Patients with left-sided svPPA outnumber those whose svPPA begins on the right side by approximately two to one. The reason for this difference may be that right-sided temporal degeneration is psychiatrically flavored and that these patients are less likely to be seen in neurological settings. When the disorder begins on the right side, psychiatric features predominate, with loss of empathy, atypical depressive features, and inability to recognize emotions in faces being common features of the disease. The ability to recognize familiar faces is lost early. Regardless of which hemisphere is affected first, the contralateral anterior temporal lobe becomes involved with disease progression [27].
Non-fluent variant primary progressive aphasia
The nfvPPA subtype accounts for approximately 25% of all FTD, is intermediate in rates of progression (4.3 years from diagnosis) and genetic propensity, and has a high association with CBD and PSP. Most patients show tau inclusions postmortem [28].
Patients with nfvPPA have selective left frontoinsular degeneration. First symptoms include decreased output for words, shortened phrase length, and deficits in articulation. Deficits in the understanding of grammar are common. Many patients exhibit speech apraxia: a deficit in articulatory planning in which the patients are unable to direct speech musculature to produce sounds in a proper sequence. Patients are usually able to maintain social decorum throughout most of the illness. When supranuclear gaze palsy, frequent falls, dysphagia or asymmetric parkinsonian signs such as focal dystonia or alien hand are seen, the association between the nfvPPA syndrome and CBD or PSP-S becomes apparent. Some patients evolve from nfvPPA to classical CBD or PSP over a fairly short period of time. Most patients with nfvPPA show tau pathology at postmortem [28]. Some patients with bvFTD also show PSP or CBD, whereas few patients with svPPA are shown to have characteristics of PSP or CBD [29, 30].
Pathological findings in frontotemporal lobar degeneration
Two major types of pathological changes are observed in FTLD: gross morphological atrophy in the frontal and anterior temporal lobes, and microscopic changes, including any or all of the following: gliosis, inclusion bodies, swollen neurons, and microvacuolation. These changes are non-specific, occurring in different forms of FTLD. More specifically, there are different neuronal and glial protein aggregates that characterize different forms of FTLD: those containing tau, TDP-43, FUS or dipeptide repeats.
Gross anatomical changes
In FTLD, gross anatomical changes range from a mild to a severe decrease in overall brain weight, associated with focal atrophy of the frontal and temporal lobes. Symmetric atrophy of the frontal lobes is characteristic of bvFTD, while asymmetric atrophy (left > right) is consistent with nfvPPA (frontal lobes) and svPPA (temporal lobes). Thinning of the cortical ribbon and discoloration of white matter may also be observed [31]. Ventricular enlargement is often present, as well as pallor of the substantia nigra.
Seeley and colleagues [32] suggested that large neurons found in Layer 5b of frontoinsular and anterior cingulate cortex, neurons most extensively described by von Economo, may be the first cells to degenerate in FTD. The von Economo neurons are found in the greatest concentration in humans compared with other great apes, cetaceans, and elephants. They are very sparse or absent in other species. The large size and small dendritic tree of von Economo neurons suggest that they may be responsible for the quick transmission of signals from paralimbic into adjacent frontal regions involved with higher-order cognitive processes. Krill and Halliday described a pathological staging system based on the degree of focal brain atrophy ranging from Stage 1 (mild atrophy of the anterior frontal cortex and hippocampus) to Stage 4 (severe frontotemporal lobar and hippocampal atrophy, together with prominent atrophy of the basal ganglia, thalamus, and a marked loss of white matter) [33]. This staging system correlated well with clinical symptomatology, disease duration, and severity of deficits.
Microscopic findings
FTLD-tau
Tau is a protein that binds and stabilizes microtubules and is involved with the transportation of proteins and nutrients along axons [34]. In humans, there are six isoforms of tau generated by alternative splicing. Normally, the isoforms are evenly distributed between 4 repeat (4R) tau, and 3R tau, which differ by the absence or presence of a long repeat at exon 10. Acetylation followed by hyperphosphorylation of tau leads to its aggregation, which is toxic to cells. The toxicity of aggregates versus the loss of tau function remain two potential mechanisms for neuronal death. Diamond and colleagues have suggested that tau spreads from cell to cell in a prion-like manner. While neurofibrillary tangles in Alzheimer’s disease (AD) are associated with aggregates of both abnormally phosphorylated 3R and 4R tau, tau-positive FTLD are associated predominantly with aggregates of 4R tau, with the exception of Pick’s disease [35]. There are four major FTLD subtypes associated with tau aggregates: Pick’s disease, CBD, PSP, and argyrophilic grain disease.
Despite the origins of the FTLD classification, only about 20% of patients diagnosed with FTLD will show the classical Pick pattern at autopsy [36]. In classical Pick’s disease, much of the gross atrophy seen at pathology is a result of a severe and often complete loss of large pyramidal cells in cortical layer III, and the small pyramidal and non-pyramidal cells of layer II [10]. Pyramidal cells in layer V may also be shrunken. The most severe loss of synaptic density is found in the superficial frontal layers. White matter changes include loss of myelin and axons. Remaining neurons show one of two possible distinctive histological features: swelling (called “ballooned” or Pick cell) and an inclusion within the perikaryon, most often in layer II (Pick body). Pick bodies are usually found in limbic, paralimbic, and ventral temporal lobe cortex, but they may also be seen in anterior frontal and dorsal temporal lobes. Pick bodies are composed of randomly arranged filaments of mainly 3R tau.
CBP and PSP are both 4R tauopathies and associated with behavioral, frontoexecutive, and extrapyramidal changes. While both conditions are characterized by the selective vulnerability of frontal–subcortical and the basal ganglia circuitries, there are some differences between the two. In PSP, the midbrain, pons, and cerebellum are preferentially involved, and the early midbrain involvement resulting in supranuclear gaze abnormality is a useful predictor of underlying PSP pathology. Cortical atrophy is relatively mild in PSP [37]. In CBD, the brain has ballooned or swollen neurons similar to those seen in Pick’s disease and astrocytic plaques. These ballooned neurons may be found throughout the neocortex, but mostly in the superior frontal and parietal lobes, including primary motor or sensory cortex. There is also neuronal loss and gliosis in affected regions, often in the basal ganglia.
Argyrophilic grain disease (AGD) is the most frequent but most poorly understood of the FTLD-tau syndromes. It is associated with a wide range of clinical syndromes ranging from mild cognitive impairment to bvFTD or PSP, often with slow progression. It often coexists with other neuropathology such as AD, ALS, PSP, and CBD [38, 39]. More research is needed to better understand the role of AGD in these neurodegenerative conditions.
FTLD-TDP
Before TDP-43 was discovered, it was known that 50% of FTLD cases were negative for tau inclusions but positive for ubiquitin; this group of FTD patients were designated as FTLD-U. In 2006, Neumann and colleagues discovered that the hyperphosphorylated, ubiquinated, and cleaved form of the TARDBP protein was the major protein responsible in FTLD-U [40]. The same TDP-43 inclusions were also found in ALS patients, linking FTD and ALS as pathologically related disorders. TDP-43 is normally a nuclear protein, binds both DNA and RNA and is likely involved in the regulation of transcription, mRNA splicing, and translational regulation.
There are four major subtypes of FTLD-TDP [41]. Type A TDP-43 is associated with dystrophic neurites, neuronal cytoplasmic TDP-43 inclusions, and sometimes lentiform neuronal intranuclear inclusions and is found in patients with progranulin (GRN) mutations, sporadic bvFTD, and PNFA which are negative for tau. Type A pathology is also seen in seemingly sporadic forms of nfvPPA and in some cases of FTD-ALS due to C9ORF72 mutations. TDP-43 type B is typically found in patients with FTD and ALS and is commonly associated with C9ORF72 mutations. TDP-43 type C is seen mainly in svPPA [42]. Type D TDP is seen in valosin-containing protein (VCP) mutation carriers with bvFTD, inclusion body myositis, and Paget’s disease of bone [43]. The diversity in the etiologies and subtypes of TDP-43 aggregation in FTLD suggests that there are different mechanisms leading to neurodegeneration that may require different therapeutic approaches.
FTLD-FUS
Approximately 5% of bvFTD patients have aggregates that stain negatively with tau and TDP-43 but stain positively for the FUS protein [44]. FUS is a DNA- and RNA-binding protein and probably has functions that parallel those of TDP-43. FUS is normally a nuclear protein but in FTLD, the FUS aggregates within the cytoplasm of neurons. Although FUS mutations can cause familial ALS, most patients with FTLD-FUS have no family history of FTD or ALS, and do not exhibit ALS during life. Instead, most FTLD-FUS patients manifest as bvFTD, with a young age of onset and higher prevalence of psychotic symptoms [45].
Genetic findings in frontotemporal lobar degeneration
Approximately 40% of patients with FTD have a positive family history for dementia, a neuropsychiatric syndrome or a movement disorder, and a majority of familial FTD patients exhibits an autosomal dominant transmission pattern [46]. The three genes most commonly mutated in familial forms of FTD are the microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. Less commonly associated genes include VCP, charged multivesicular body protein 2B (CHMP2B), TARDBP, and FUS.
MAPT
The first genetic discovery related to the FTLD syndrome was the finding that mutations of MAPT could cause an autosomal dominant FTD syndrome previously grouped under the classification “frontotemporal dementia with parkinsonism linked to chromosome 17” (FTDP-17) [47, 48]. Subsequently, more than 40 MAPT mutations have been identified in different families and the clinical spectrum of FTD caused by MAPT mutations is wide, including bvFTD, svPPA, nfvPPA, PSP, and CBD. There is significant variability in the clinical syndrome even among members of the same family. Patients with MAPT mutations typically present at a younger age (around age 50), often with a long prodrome of psychiatric illness such as addictive behaviors, anxiety, and loss of empathy, before developing a frank dementia. MAPT mutations are highly penetrant and rarely found in patients without a family history of FTD, dementia or parkinsonism [49]. The brains of MAPT patients tend to exhibit symmetrical anterior frontotemporal degeneration [50], and because of the involvement of the basal ganglia some patients begin with a parkinsonian syndrome, with ophthalmoplegia suggestive of PSP being very common.
Many of the tau mutations that are involved in FTLD are clustered around exons 9, 10, 11 or 12, and may be missense or deletion in the exonic and intronic regions. The ultimate result of these mutations is alteration of the ratio of 3R to 4R tau in the brain or the binding affinity of tau to microtubules [51]. In addition to pathogenic mutations of tau, there are other MAPT genetic variations that are over-represented in FTD-spectrum disorders. MAPT is located within one of two haplotypes (H1 and H2),DNA segments that are inherited together as a unit. The H1/H1 genotype is over-represented in patients with PSP and CBD compared with healthy controls, suggesting an increased susceptibility conferred by this genotype. Similarly, A152T, which is a rare variant of MAPT, appears to predispose individuals to PNFA, CBD, PSP, and bvFTD. Both the H1 haplotype and the A152T variant are thought to result in increased expression of 4R tau.
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